Genetic clue to origins of pancreas cancer

“Aggressive pancreatic tumours may be treatable with a new class of drugs,” BBC News has reported today.

Pancreatic cancer is one of the most aggressive forms of cancer, and very few patients diagnosed with the disease survive beyond five years after diagnosis, while most die within a year. However, relatively little is known about what the causes of the disease are.

This news highlights a new study in which researchers set out to explore new potential genetic causes of pancreatic cancer. The research involved a combination of mouse and human cell studies that looked at genes that may be involved, with results suggesting that a gene called USP9X can greatly raise the risk when not functioning normally. The role of the gene is to stop cells dividing uncontrollably, but tests in mice showed it was blocked from working in about 50% of pancreatic tumour cells in mice. The USP9X gene itself was not faulty, but proteins and other chemicals had interacted with the gene to switch it off in the tumour cells. Looking at the gene in human cancer patients showed the gene tended to be less active in tumour cells than in normal cells.

This research may be useful but, despite media claims that existing drugs may be able to remove chemicals interacting with USP9X, this study did not test a new class of drug, or indeed any drug, to see if it was effective at treating or preventing pancreatic cancer in humans. Consequently, media reports that there is a “new drug hope” for pancreatic cancer are a little premature, although the research certainly highlights some areas for future research to explore.

Where did the story come from?

The study was carried out by a large collaboration of international researchers from Europe, Australia and the USA. It was funded by Cancer Research UK.

The study was published in the peer-reviewed scientific journal Nature.

The media reporting of this study was generally balanced. However, some reports that existing drugs “could be an effective way of treating pancreatic cancer” are not proven by this laboratory study, which explored the mechanisms that may be behind pancreatic cancer rather than testing any drugs in patients with the condition.

What kind of research was this?

Pancreatic cancer is one of the most aggressive and hard-to-treat forms of cancer, and patients diagnosed with the condition generally have a low rate of long-term survival. The causes of pancreatic cancer are relatively unknown, so in recent years there has been a great deal of research in this area.

This latest research was a laboratory study investigating the role different genes might have in the cause and progression of pancreatic cancer. It involved experiments in both mice bred to have pancreatic cancer and extracted human pancreatic cancer cells. It also looked at the genetics of the cells of pancreatic cancer patients, although it did not perform any direct experiments in living humans.

Within human DNA there are sections of code that perform a specific function, and these are known as genes. These genes contain instructions for making proteins, which then go on to perform a host of important functions in the body. Mutations within genes can either stop the body making key proteins, or cause the body to make abnormal versions of proteins so that they do not work in a typical way. The authors said that previous research established that pancreatic cancer is associated with common mutations in genes called KRAS, CDKN2A, TP53 and SMAD4.

The authors said that, out of all these mutations, KRAS was most commonly associated with pancreatic cancer, and therefore researchers sought to investigate what other genes worked with KRAS to cause or accelerate pancreatic cancer. The normal function of the KRAS gene is to produce a protein involved in regulating cellular division, as occurs when cells reproduce themselves.

What did the research involve?

Mice were bred with genetic mutations in a gene called KRAS within their pancreas cells, which meant they would be highly likely to develop cancer of the pancreas during their lives. The scientists then engineered a selection of 20 further candidate genes to be mutated in each mouse's pancreas to see how they influenced cancer development in their pancreatic cells. The basic premise is that there might be some interaction between these mutant genes and KRAS that would encourage the development of pancreatic cancer.

After testing whether these various mutations increased the risk of cancer developing in the pancreatic cells of living mice, the researchers further tested those genes that appeared to have the greatest influence, to understand better how they worked. To determine whether the most important candidate genes in mice were also important in human cancer, the scientists used human pancreatic cells taken from patients during surgery to remove their cancer. The cancer cell DNA of 100 people was isolated and tested to see if it had errors in any of the candidate genes previously highlighted in the mice.

The activity of candidate genes was also tested in a second cohort of 42 patients with pancreatic cancer to see if the gene was being “read” correctly by the cellular machinery to produce proteins in a normal way. The protein levels of a further 404 patients with pancreatic cancer were analysed to see what proteins were elevated or reduced in these cells, and how these levels might relate to the genetics of the cells. The protein levels of the cancerous cells were compared with normal cells to highlight differences.

The researchers then performed a statistical analysis of their study results, which was done in an appropriate manner.

What were the basic results?

The key findings of the study were as follows:

The most commonly mutated gene out of the 20 in the mice model of pancreatic cancer tested was called USP9X. This was mutated (and therefore inactive) in over 50% of the mouse tumours tested.

In the mice cells that were engineered to have no USP9X gene there was a faster progression of pancreatic cancer.

In human cells, the researchers found that in the majority of cases (88 out of 100) the genetic code of the USP9X gene was normal, therefore the problems were likely to be in the regulation of the gene – how fast or slow the cell machinery reads the genetic code to produce proteins from it.

In these cases, low expression of USP9X and low protein levels from the gene correlated with worse survival after surgery for pancreatic cancer.

In the second cohort of 42 patients with pancreatic cancer, low expression of USP9X correlated with cancer that was “metastatic”, which meant it had spread to other parts of the body. Generally, metastatic cancers are harder to treat and pose greater danger to patients.

In a subset of 404 patients with pancreatic cancer, the level of protein produced when the USP9X is read by the cellular machinery was lower than in normal pancreatic cells.

How did the researchers interpret the results?

The researchers concluded that “USP9X is a major tumour suppressor gene” that has not previously been implicated in pancreatic cancer. A tumour suppressor gene means that, when functioning correctly, the gene stops the cell becoming cancerous, but if the gene or its regulation goes wrong, it can lead to cancer. The authors also concluded that the USP9X gene is inactivated in cancer cells not because it has mutations (mistakes in its genetic code) but rather because chemicals have attached to the surface of the gene to turn it down or off. These attached substances, known as “tags”, prevent it from producing proteins in a normal way.

Conclusion

This laboratory study has examined various genetic factors in mice, extracted cells and living patients to show that the USP9X gene may have a role in some people with pancreatic cancer. In human pancreatic cancer cells, the USP9X gene was found to produce lower levels of a cancer-suppressing protein than in normal pancreatic cells. Furthermore, the mice model showed that reducing the function of the USP9X gene accelerated the progression of cancer. Taken together, this suggests that USP9X has an important role in a subset of pancreatic cancers that have problems in the regulation of this gene.

This study is at an early stage and would need to be confirmed in more people to see how common this mutation is in people with pancreatic cancer, and whether the regulation of this gene is similar in most patients. Cancer is a complex disease and typically involves numerous genetic mutations and problems with genetic regulation. Therefore, even if a method or drug was available to ensure USP9X functions normally, other genes may also have a role in pancreatic cancer. Furthermore, there is likely to be a range of environmental factors that also influence a person’s risk of developing pancreatic cancer to some extent.

In the various media reports, clinical experts are quoted as having said that some existing cancer drugs that work to strip away genetic tags “are showing promise in lung cancer”. Hence, some commentators have suggested that these drugs may work in people with USP9X inactivity caused by genetic tags.

This research may be useful but it is important to note that this study did not test a new class of drugs to see if it was effective at treating or preventing pancreatic cancer. Consequently, media reports that there is a “new drug hope” for pancreatic cancer are a little premature. For example, USP9X may not be the only factor that increases an individual’s risk of cancer, so even if a drug could successfully reverse tagging of the gene it would not guarantee that they would have no risk of the disease.

However, this study does highlight a gene that was not previously thought to be important in pancreatic cancer, and this will be a useful focus for future research to understand better the biology of pancreatic cancer.